This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The purpose of this project is to gain a stronger fundamental understanding of how antigen presenting cells in the intestine function to modulate mucosal tolerance and immunity. The central hypothesis that drives this research is that intestinal lamina propria macrophages promote the induction of regulatory T cells and mucosal tolerance. Numerous observations have established that the pathogenesis of IBD is a multifactorial process encompassing at least three major interacting elements: genetic susceptibility factors, environmental conditions, and altered mucosal immune function. While genetic factors and the environment are incredibly difficult to investigate and control, significant attention and research investigation has been focused on understanding mucosal immune responses in IBD with the working hypothesis being that intestinal inflammation results from a breakdown in immune tolerance to normal autologous flora. While there is increasing understanding of the factors that contribute to the pathogenesis of IBD, there is an urgent need for more thoroughly understanding protective factors that control inflammation in order to design more efficacious treatments and to even begin to envision prevention of IBD. An important challenge remains the ability to maintain critical balance between enforcing intestinal tolerance, while allowing for appropriate mucosal immune responses to pathogenic microbes. Mucosal resident antigen presenting cells, particularly dendritic cells (DCs) and macrophages, hold great promise in this regard because they can uptake enteric bacteria and induce distinct types of immune responses. In essence, mucosal APCs are sentinels situated just beneath the epithelial barrier and are capable of initiating and orchestrating intestinal immune responses.